The dermal structures of humans and other animals are often the site of infections or attachments by other living organisms. Dermal structures include, but are not limited to, skin, hair, hair follicles, cornea, sclera, organ linings, pleural coverings, dura, toenails, fingernails, hooves, horns, mucous membranes, and other cellular structures made from epithelial cells or keratinized structures. Organisms that live in or on the dermis or dermal structures of humans and animals include microorganisms such as yeasts, fungi, bacteria, viruses, mycoplasma, and insects such as dust mites, ticks, lice and other arthropods.
The presence of these organisms in and on dermal structures often cause a range of changes, from merely unsightly to pathological conditions, to the dermis and dermal structures, and can interfere with the functions of the dermis and dermal structures of the host organism. Additionally, the presence of these organisms can result in immunological responses by the host and cause secondary problems at the site or a general response throughout the entire host organism. Thus, there is a need to prevent infection or attachment by such organisms, control the amount of infection or attachment by such organisms, treat the affected sites, and prevent the re-infection and re-attachment by such organisms from the environment.
One of the most common and difficult to treat dermal conditions is infection of nail structures. The finger and toenails of humans are specialized tissue structures that are closely related to claw and hoof tissues in animals. The nails constitute an important protective structure at the distal ends of the fingers and toes that shield the highly sensitive extremities from triggering pain or sensation on contact with the external environment. Nails also function as an important tool that is used to increase the range of dexterous accomplishments. Humans have developed great pride in the function and appearance of nails. In many cultures, painting and decoration of the nails of both the hands and feet are common place.
Nails, like most anatomical structures of the body, are susceptible to disease processes. One of the pathological conditions that is common for humans is caused by microbial invasion of the nail or surrounding tissues. Although the condition is not life threatening, infection of these tissues can compromise the appearance and the function of the affected nail. One such condition results from the invasion of the tissues by one or more of several fungi. Fungal involvement in nail infection has been termed onychomycosis.
Onychomycosis, or fungal infection of the nail, is the most common cause of nail dystrophy. The incidence of the condition has been difficult to determine largely because it is not life threatening and rarely is reported. It has been estimated that the incidence ranges from 3% to 23% of the total population in western cultures. There is no clear understanding of the circumstances that predispose to this condition. It has been suggested that there is a relationship between trauma to the nail region and the occurrence of infection. However no studies have confirmed this hypothesis.
It is known that certain lifestyle and climatic situations seem to contribute to onychomycosis. One example is the greater than 80% occurrence rate of onychomycosis in the general population in outlying northeastern areas of Russia where long cold winters are encountered. This is likely due to the necessity of using heavy protective footwear for prolonged periods to protect the feet from the cold. This exposes the foot, and more particularly the nails, to prolonged moist warm conditions that may encourage the growth of the fungi.
In western cultures it is well known that there is an age related distribution in the incidence of onychomycosis. The condition is much more prevalent in elderly individuals. Indeed it has been estimated that 80 to 90% of the elderly in the U.S. and Canada have at least one or more of their nails involved. One reason for the increase with age is that onychomycosis poorly responds to treatment, hence is seldom treated so there is an accumulation of cases. Other factors that may contribute to the increase with age are a general waning of innate and specific immunity to fungal pathogens as well as an increased accumulation of comorbidities that may contribute to invasion by the fungal pathogens associated with onychomycosis.
Onychomycosis is a dystrophic condition of the nails of the feet and hands. Fungal infection of the nails results in characteristic changes in the appearance to the structure. The appearance is often used to describe the degree of severity of the infection. Clinicians often use appearance alone in differential diagnosis of the condition. Knowledge of the state of the disease is often useful in determining the course of treatment and the likelihood of success in the management of the disorder. The common forms of the disease are listed in Table 1.
TABLE 1State of diseaseTissue involveSeverityDistal Lateral SubungualFungal invasion at theSuperficialOnychomycosisextreme distal end of(DLSO)the nail bed.Proximal SubungualFungal invasion at theSuperficial to severe.Onychomycosisproximal end of theMost often in(PSO)nail bed.immunocompromisedpeople.White SuperficialNail plate only result-Superficial to severe.Onychomycosising in discrete to ex-(WSO)tensive white patchesor streaks in the nail.Total DystrophicEntire nail bedSevere.Onychomycosisinvolved.(TDO)EndonyxPartial or completeSuperficial to severe.involvement of nailplate.
These different presentations are important in predicting the outcome of a treatment strategy. The anatomy of the nail and its supporting structures profoundly influence the effectiveness of treating the tissues to rid them of the fungal pathogens. The reason for this is that nail structure and anatomy are complex and, to some degree, are isolated from systemic circulation. Furthermore the nail plate is relatively impermeable to penetration by topical agents.
The anatomy of the human nail is important for the understanding of the process that results in onychomycosis. The nail unit is a form of specialized epidermal tissue. The nail apparatus, which comprises all the elements colloquially referred to as “the nail”, is composed of distinct structural elements. The most prominent structure of the nail apparatus is referred to as the nail plate which is a thin hard flexible structure that emerges from skin folds at the extremities of the digits. The nail plate is produced by the nail matrix situated in the proximal fold. The matrix causes nail plate elongation through proliferation of its epidermal-like cells. The lateral folds hold the nail plate in an orientation so that elongation proceeds towards the distal end of the extremity. The nail plate grows at the rate of 1 mm (toe nail) to 3 mm (fingernail) per month. The nail plate is translucent in appearance, almost always convex in shape and approximately 0.2-0.6 mm thick. It is composed of approximately 25 layers of dead, keratinized cells that originate from the matrix. These dead cells are held tightly together by intercellular linkages resulting in a coalescent dense hard plate with a smooth dorsal surface. The ventral side of the nail plate is relatively irregular which facilitates attachment of collagen fibers which serve to anchor the nail plate to the nail bed. Nail plate elongation continues toward the distal end of the digit where it parts from the nail bed at a point termed the hyponychium.
The nail plate, chemically, is largely protein along with approximately 10-30% aqueous moisture. Moisture content in the nail plate is directly proportional to the moisture content of the environment. Immersion in water will increase moisture content as will occlusion of the surface so as to prevent evaporation. The nail plate also contains between 0.1 to 1% lipid. There is no central circulation or lymphatic drainage associated with the nail apparatus. However the tissues proximal and lateral, and those beneath the nail bed are highly vascularized. Notwithstanding, the matrix is the only viable component of the nail and is the only structure supported by systemic circulation. The remainder of the nail apparatus is non-viable and is separated from systemic support by a layer of collagen fibrils and nail plate substrate.
Under normal circumstances the nail plate and hyponychium present a formidable barrier to microbial penetration. Indeed, most cases of onychomycosis originate in the distal area of the nail which implies a disturbance to the tight junction at the hyponychium. This probably provides fungi access to the region beneath the nail plate that is rich in organic substrate sufficient to support the growth of the fungi. Less frequent, is the direct fungal penetration into the nail plate. Trychopyton mentagrophytes can invade in this way because it produces enzymes that are capable of degrading the protein matrix of the nail plate, thereby enabling the fungus to penetrate directly into the substrate. In either case the fungi enter a privileged region that is largely devoid of natural resistance mediated by the immune system since there is no systemic circulation to the tissues. Moreover, the absence of circulation also restricts the ability of delivering systemic anti-microbial agents effectively to the specific sites where the fungi inhabit.
Onychomycosis is an active disease process that involves the growth and replication of saprophytic fungi in the nail apparatus. Most often the fungi are in the non-viable region between the nail plate and the nail bed. Accurate diagnosis of the condition requires the microscopic examination and culturing of specimen material taken from the affected region. Typically scrapings from the site of infection are first digested in a strong solution of KOH, mounted on microscope slides with a suitable stain specific for fungal mycelium, and then visualized for typical structures common to dermatophytes. In addition, differential diagnosis is greatly enhanced by propagation and identification of fungi using in vitro culturing methods. However, microscopic examination and in vitro culture are time consuming and expensive. Therefore many clinicians will make an imperical diagnosis based on the appearance of the affected nails, lifestyle factors, and age of the individual. This approach may lead to a misdiagnosis of cases resulting in inappropriate and dangerous treatment modalities. There is need for a treatment that is safe and economical that can be implemented with little or no risk should the original diagnosis be incorrect.
The current systemic and the topical methods for the management of onychomycosis are expensive, have low success rates and in many cases expose the user to considerable risk of central organ damage. This is predominately due to the need to deliver sufficient active agent to the individual to achieve an inhibitory concentration in the non-viable regions where the fungi resides. In most cases delivery and accumulation of the active agent is dependent upon diffusion through non-viable and non-vascularized substrate (nail plate, or anchor protein zone of the nail bed). This often has meant persistent administration of the agent with its concomitant risk of systemic toxicity.
The alternative to a direct attack on the fungi is the removal of its privileged habitat. This can be accomplished by removal of the nail plate which provides both nutrient substrate and protection to the fungal parasite. Surgical ablation is still recommended by some as quicker, and better accepted than chemical ablation which is essentially painless. Others condemn it and say chemical ablation is the only way it should be done. Chemical ablation is done by covering the skin around the nail for protection and then applying 40% urea to the nail. An occlusive dressing is then put on and left for a week at which time the patient returns to the doctor for removal. The expense includes a minimum of two doctor visits plus the “procedure” cost. It is effective at removing the nail but it is known to have a fairly high failure rate unless combined with drug treatment. Furthermore it requires between 6 months to a year for the complete outgrowth of new nail plate and a return to a normal appearance of the nail apparatus. It is also somewhat controversial as to its effectiveness as there are no studies showing actual incidence of cure.
The use of oral drugs has lead to the achievement of excellent penetration and accumulation of active agents within the nail after prolonged (months) duration of drug administration. Topical administration has also resulted in good penetration and accumulation of the active. Drug levels have been recorded by direct assay for the active agents, yet in both topical and oral administration there has been a dismal record of cure rate. Complicating evaluation of true cure rate is that “cure” has been ill-defined. In some studies it is taken to mean the achievement of a normal looking nail apparatus whereas in other cases it is taken to mean the elimination of microscopic or culture detectable fungi in specimens collected from the treatment site. Regardless of the method of assessment there is clear recognition that the high cost of treatment, the poor level of outcome, and the concomitant risk of side effects from the therapy have identified that there is a need for a safe, effective, and economic treatment modality for onychomycosis.
There is also a need for treatments for other dermal conditions that are easily used and applied by patients because the treatment times are often long and extended. An ideal treatment modality for onychomycosis and other dermal pathologies would be effective and sufficiently straightforward so that it encourages a high degree of patient compliance. A simple and relatively short duration of administration of an agent targeted for the organism responsible for the pathology should be highly effective at controlling or eliminating the disease-state. Effective topical treatment of the conditions requires successful penetration of the active agent through the nail plate or dermal layers to the zone most commonly harboring the organism. An effective treatment would include the penetration and accumulation/maintenance of an effective concentration of active agent in the growth site and habitat of the unwanted organism.
Compositions are needed that are effective for treatment of unwanted organisms causing pathological conditions in the skin and dermal structures. Such compositions can be used in methods for preventing infection or attachment, treating existing conditions, and preventing re-infection or re-attachment of organisms in the environment. Such compositions should be well tolerated by the patients.